Fluticasone propionate aqueous nasal spray is safe and effective for children with seasonal allergic rhinitis

INTRODUCTION: Fluticasone propionate aqueous nasal spray, a new topical corticosteroid preparation, is effective when given as 200 micrograms once daily in patients (> 12 years of age) with seasonal allergic rhinitis. STUDY OBJECTIVE: To evaluate the efficacy and safety of fluticasone proprionate aqueous nasal spray in children aged 4 to 11 years with seasonal allergic rhinitis. STUDY DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group. PATIENTS: Two hundred fifty children aged 4 to 11 years with moderate-to-severe nasal symptoms, a positive skin test reaction to a late-summer or autumn allergen, a history of seasonal allergic rhinitis, and documentation of an unsatisfactory response to conventional treatment. INTERVENTIONS: Children were randomly assigned to receive fluticasone propionate, either 100 micrograms or 200 micrograms, or placebo, given by intranasal spray once daily in the morning for 14 days. MEASUREMENTS AND RESULTS: Severity of nasal symptoms (obstruction, rhinorrhea, itching, and sneezing) was recorded on visual analog scales by investigators at weekly visits and by patients (or adult guardian) daily in the evening. According to investigator and patient ratings, both fluticasone propionate 100 micrograms/d and 200 micrograms/d lowered total nasal symptom scores when compared with placebo. Both dosages of fluticasone propionate were more effective than placebo on the basis of investigator-rated overall clinical evaluation of efficacy at the end of treatment, with significant improvement (as opposed to moderate or mild improvement, no change or worsening) noted in 21% to 29% of the active-treatment groups vs 9% in the placebo group. There were no significant differences between the two fluticasone propionate dosages in any efficacy measurement. Morning plasma cortisol concentrations and frequency of drug-related adverse events were similar in the fluticasone propionate and placebo groups. CONCLUSION: In children as young as 4 years, 100 micrograms of fluticasone propionate aqueous nasal spray given once daily is as effective as 200 micrograms given once daily, the usual adult dose for the treatment of seasonal allergic rhinitis. Both fluticasone propionate dosages were well tolerated and neither dosage appears to interfere with the hypothalamic-pituitary-adrenal axis in children.     

Antianginal response to once-daily diltiazem CD in patients receiving concomitant beta-blockers, long-acting nitrates, or both. Diltiazem CD Study Group

STUDY OBJECTIVE: To determine the safety and efficacy of diltiazem CD 180 mg administered once/day in patients with chronic stable angina inadequately controlled with P-blockers, long-acting nitrates, or both. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. SETTING: Medical clinics in the private and academic sectors. PATIENTS: Of 172 patients, 170 completed the 2-week double-blind treatment period. INTERVENTION:. Patients received either diltiazem CD 180 mg or placebo once/day in combination with existing antianginal therapy. MEASUREMENTS AND MAIN RESULTS: The time to termination of exercise tolerance testing, 24 hours after the dose increased significantly in the diltiazem CD group (37.2 sec) compared with the placebo group (21.3 sec, p=0.0438). Time to onset of angina during exercise testing also increased (57.6 vs 35.0 sec, respectively, p=0.0324), as did time to moderate angina (37.5 vs 20.6 sec, respectively, p=0.0354). The rates of total angina attacks and of angina attacks on exertion were significantly reduced in the diltiazem CD group versus placebo (p<0.05). Significant reductions in systolic and diastolic blood pressures and heart rate-blood pressure product measured at rest, submaximum exercise, and exercise termination were observed in diltiazem CD-treated patients compared with placebo (p<0.05). The frequency of treatment-related adverse events was identical in the two groups, 15.1%. CONCLUSION: Diltiazem CD 180 mg once/day is an effective, safe, and beneficial initial dosage when added to existing antianginal therapy.     

Intranasal fluticasone propionate is more effective than terfenadine tablets for seasonal allergic rhinitis

BACKGROUND: We compared the efficacy and tolerability of the intranasal corticosteroid fluticasone propionate with that of the antihistamine terfenadine in patients with seasonal allergic rhinitis. METHODS: Two hundred thirty-two adults and adolescents with seasonal allergic rhinitis received intranasal fluticasone propionate (200 micrograms once daily), terfenadine tablets (60 mg twice daily), or placebo for 2 weeks in a double-blind, randomized, parallel-group study. Main outcome measures were clinician- and patient-rated individual and total nasal symptom scores (based on ratings of nasal obstruction, sneezing, nasal itching, and rhinorrhea); clinician-rated overall response to therapy; changes in nasal inflammatory cell counts; adverse events; and morning plasma cortisol concentrations. RESULTS: Both clinician- and patient-rated total and individual nasal symptom scores were significantly lower in the fluticasone group than in either the terfenadine group or the placebo group at nearly every measured time point throughout the treatment period. After 2 weeks of therapy, clinician-rated total nasal symptom scores decreased by 49% in the fluticasone group compared with 27% in the terfenadine group and 19% in the placebo group. In general, therapy with terfenadine was not statistically distinguishable from that with placebo based on patient-rated total or individual nasal symptom scores. According to clinician ratings, 64% of fluticasone-treated patients compared with 49% and 44% of patients treated with terfenadine and placebo, respectively, experienced significant or moderate improvement. A greater percentage of fluticasone-treated patients compared with either terfenadine- or placebo-treated patients experienced reductions in intranasal eosinophil and basophil counts after 2 weeks of therapy. No unusual or serious drug-related adverse events were reported. Morning plasma cortisol concentrations after 2 weeks of therapy did not differ among groups. CONCLUSION: Fluticasone aqueous nasal spray, a well-tolerated corticosteroid preparation that can be administered once daily, is more effective than terfenadine tablets or placebo in controlling symptoms of seasonal allergic rhinitis.     

Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial

PURPOSE: To study the efficacy and safety of various dosages of metformin as compared with placebo in patients with type II diabetes mellitus. PATIENTS AND METHODS: A 14-week, multicenter, double-blind, dose-response study was conducted. After a 3-week, single-blind, placebo-controlled washout, 451 patients with fasting plasma glucose levels of at least 180 mg/dL were randomized to receive an 11-week course of placebo or metformin given at 500, 1000, 1500, 2000, or 2500 mg daily. RESULTS: Metformin improved glucose variables as compared with placebo. The adjusted mean changes in fasting plasma glucose from baseline associated with each metformin group at week 7, 11, or at endpoint exceeded those associated with placebo by 19 to 84 mg/dL at dosages of 500 to 2000 mg daily, respectively. The corresponding between-group differences in glycated hemoglobin (HbA1c) ranged from 0.6% to 2.0% at dosages of 500 to 2000 mg daily, respectively. All between-group differences were significant (P < 0.05) for both fasting plasma glucose and HbA1c at week 7, week 11, and endpoint, except for the difference between placebo and metformin 500 mg in fasting plasma glucose at endpoint (P = 0.054). Treatment-related adverse events occurred in 15% of patients in the placebo group and in 28% in the metformin group (P = 0.02); these were primarily manifested as digestive disturbances, such as diarrhea. CONCLUSIONS: Metformin lowered fasting plasma glucose and HbA1c generally in a dose-related manner. Benefits were observed with as little as 500 mg of metformin; maximal benefits were observed at the upper limits of the recommended daily dosage. All dosages were well tolerated. Metformin appears to be a useful therapeutic option for physicians who wish to titrate drug therapy to achieve target glucose concentrations.     

Propranolol in hypertension: a dose-response study

The effect of propranolol was studied in a double-blind crossover trial in 24 carefully selected hypertensive outpatients. Each patient received propranolol 60 mg/day, 120 mg/day, 240 mg/day, and placebo for four weeks each according to a randomised sequence. Propranolol 60 mg/day was no better than placebo in reducing blood pressure. The effects of propranolol 120 mg/day and 240 mg/day were not significantly different. Both doses reduced lying blood pressure by about 20/10 mm Hg from an initial level of 173/104 mm Hg. No difference was detected between the effects of the different doses of propranolol and placebo on weight or on the occurrence of adverse reactions.     

Sulpiride infused into the nucleus accumbens posttraining impairs memory of spatial water maze training

A randomized, double-blind study of valaciclovir for suppression of recurrent genital herpes was conducted among 1479 immunocompetent patients. Patients were randomized to receive valaciclovir (250 mg, 500 mg, or 1 g once daily, or 250 mg twice daily), acyclovir (400 mg twice daily), or placebo, for 1 year. All valaciclovir dosages were significantly more effective than placebo at preventing or delaying recurrences (P < .0001). There was a dose-response relationship (P < .0001) across the once-daily valaciclovir regimens. Twice-daily valaciclovir and acyclovir were similar in effectiveness. Subgroup analysis showed that patients with a history of < 10 recurrences per year were effectively managed with 500 mg of valaciclovir once daily. One gram of valaciclovir once daily, 250 mg of valaciclovir twice daily, or 400 mg of acyclovir twice daily were more effective in patients with > or = 10 recurrences per year. Safety profiles of all treatments were comparable. Thus, valaciclovir is highly effective and well tolerated for suppression of recurrent genital herpes. Once-daily regimens offer a useful option for patients who require suppressive therapy for management of genital herpes.     

Risedronate

Risedronate is a pyridinyl bisphosphonate that can be administered orally in lower dosages than other antiresorptive bisphosphonates. Like others of its class risedronate inhibits osteoclast-mediated bone resorption. In experimental models of osteoporosis, risedronate inhibited bone loss and improved trabecular architecture. In patients with Paget's disease, pain diminished or disappeared and serum alkaline phosphatase levels decreased after treatment with oral risedronate 30 mg/day for < or = 3 months. Risedronate 30 mg/day orally for 2 months significantly reduced pain, whereas etidronate 400 mg/day orally for 6 months tended to reduce pain, in a randomised double-blind trial of patients with Paget's disease. Oral risedronate 5 mg/day for < or = 2 years increased bone mass in postmenopausal women with low or normal bone mass. Risedronate 2.5 mg/day prevented bone loss in postmenopausal women treated with glucocorticoids for rheumatoid arthritis. The incidence of gastrointestinal or other adverse events was similar in patients treated with risedronate or placebo in clinical trials.     

Candesartan cilexetil. A review of its use in essential hypertension

Candesartan cilexetil is completely converted to the nonpeptide angiotensin II receptor blocker candesartan during absorption from the gastrointestinal tract. Candesartan selectively blocks and dissociates slowly from the angiotensin II subtype 1 (AT1) receptor which mediates most of the known activities of angiotensin II. When administered once daily, oral candesartan cilexetil 8 to 32 mg dose-dependently and effectively reduces blood pressure in patients with mild to moderate essential hypertension. In comparative studies, candesartan cilexetil 8 mg/day was as effective as usual therapeutic dosages of enalapril, losartan potassium, hydrochlorothiazide and amlodipine. One study showed candesartan cilexetil 16 mg/day to be more effective than losartan potassium 50 mg/day. Furthermore, the combination of candesartan cilexetil with either hydrochlorothiazide or amlodipine resulted in additive antihypertensive effects. Preliminary evidence suggests that the blood pressure-lowering effects of candesartan cilexetil are associated with the prevention or improvement of end-organ damage in patients with hypertension. However, this requires further confirmation in clinical studies. Candesartan cilexetil improves insulin sensitivity in patients with hypertension and does not affect glucose homeostasis or the serum lipid profile in those with coexisting type 2 (non-insulin-dependent) diabetes mellitus. Candesartan cilexetil is well tolerated in patients with hypertension. Pooled data indicate that the tolerability profile of the drug is not significantly different from that of placebo, with headache being the most commonly reported event. Adverse events are not dose related and are mostly mild to moderate in severity. Candesartan cilexetil is better tolerated than enalapril, primarily because of a reduced incidence of cough, and was not associated with the hypokalaemia or hyperuricaemia seen with hydrochlorothiazide in a study in patients aged > or = 75 years. The drug has an adverse events profile similar to that of losartan potassium in patients with mild to moderate hypertension. Conclusions: once daily candesartan cilexetil is effective and well tolerated when used once daily (as monotherapy or in combination with other antihypertensive agents) in patients with mild, moderate or severe hypertension. Initially, however, the drug is likely to be used as an alternative to other agents in patients not responding to or intolerant of their current drug therapy.     

The efficacy of fluticasone propionate aqueous nasal spray for allergic rhinitis and its relationship to topical effects

Fluticasone propionate aqueous nasal spray is an intranasal corticosteroid for the treatment of patients with allergic rhinitis. This double-masked, double-dummy, parallel-group study was conducted to confirm that the efficacy of fluticasone propionate nasal spray is attributable to topical rather than systemic effects. A total of 304 patients with documented seasonal allergic rhinitis were randomly assigned to receive fluticasone propionate nasal spray 200 micrograms once daily (n = 77), oral fluticasone propionate 5 mg once daily (n = 73), oral fluticasone propionate 10 mg once daily (n = 77), or placebo (n = 77) for 14 days. Plasma fluticasone propionate concentrations were determined at baseline and after 14 days of treatment (day 15). Nasal symptoms were recorded daily by patients and assessed weekly by clinicians. On day 15, more patients in the oral fluticasone propionate 5-mg or 10-mg groups, compared with patients in the fluticasone propionate nasal spray group or the placebo group, had detectable plasma fluticasone propionate concentrations, and mean concentrations were higher in the oral fluticasone propionate groups. Both clinician- and patient-rated total and individual nasal symptom scores for obstruction, rhinorrhea, sneezing, and itching were significantly lower in the fluticasone propionate nasal spray group compared with either of the oral fluticasone propionate groups or the placebo group. With few exceptions, oral fluticasone propionate (5 mg or 10 mg) was not significantly different from placebo on any measures of efficacy. These findings indicate that the efficacy of fluticasone propionate nasal spray (200 micrograms once daily) in the treatment of allergic rhinitis results from direct topical effects rather than from indirect effects after systemic absorption.     

Comparison of once-daily doses of omeprazole (40 and 20 mg) and placebo in the treatment of benign gastric ulcer: a multicenter, randomized, double-blind study

OBJECTIVE: The purpose of this multicenter, randomized, double-blind study, conducted in 520 patients, was to compare the efficacy and safety of omeprazole (40 and 20 mg once daily) with placebo in the treatment of benign gastric ulcer. METHODS: Treatment with omeprazole or placebo lasted 4 wk; those whose ulcers remained unhealed continued the same treatment regimen for an additional 4 wk. The effects of therapy were determined by endoscopy and assessment of GI symptoms. Safety and tolerability were evaluated through reported adverse events, physical examinations, and laboratory tests. RESULTS: At weeks 4 and 8, the proportion of patients with healed ulcers was significantly greater in the omeprazole 40- and 20-mg groups than in the placebo group (p < 0.01). At week 8, the healing rate was significantly greater in the 40-mg group than in the 20-mg group (82.7 vs 74.8%, p < 0.05). In patients with large ulcers (>1 cm), the 40-mg regimen was associated with a significantly higher healing rate (78.9%) than both the 20-mg regimen (61.4%) and placebo (34.6%) at week 8 (p < 0.05 vs omeprazole 20 mg; p < 0.01 vs placebo). Healing rates in patients with small ulcers were similar for the 40- and 20-mg groups. Omeprazole was well tolerated, with no significant differences versus placebo in the overall incidence of clinical or laboratory adverse events. CONCLUSIONS: Omeprazole 40 and 20 mg, administered once daily, healed a significantly greater proportion of patients than did placebo. The 40-mg regimen offered significant advantages over the 20-mg regimen in patients with large ulcers.     

Eprosartan

Eprosartan is a nonpeptide angiotensin II receptor antagonist which has a high affinity for the AT1 receptor subtype. When administered at dosages of 400 to 800 mg/day (once or twice daily) for 13 weeks to patients with mild to moderate essential hypertension, eprosartan significantly reduced blood pressure compared with placebo. Eprosartan was at least as effective as enalapril 10 to 40 mg/day in a dose-titration study in patients with severe hypertension. Eprosartan is generally well tolerated; clinical trials have shown the drug to have a tolerability profile similar to that of placebo. As with other angiotensin II receptor antagonists, it does not cause cough. Eprosartan is not metabolised by the cytochrome P450 system and therefore has a low potential for drug interactions.     

Effects of oral rabeprazole on oesophageal and gastric pH in patients with gastro-oesophageal reflux disease

BACKGROUND: This study examined the dose-response effects of the new proton-pump inhibitor rabeprazole on oesophageal and gastric pH in patients with gastro-oesophageal reflux disease. METHODS: This study had a single-centre, double-blind, randomized, two-way crossover design. Twenty patients were treated for two 7-day periods separated by a 7-10-day washout period. Patients were randomly assigned to receive either 20 mg of rabeprazole once daily during the first treatment period and 40 mg once daily during the second treatment period, or 40 mg during the first treatment period and 20 mg during the second treatment period. The primary efficacy variable was oesophageal acid exposure determined by 24-hour ambulatory pH monitoring. Acid-reflux time was defined as the percentage of time over 24 h that oesophageal pH was < 4. A dosage was considered effective if reflux time was reduced to < 6%, a number which has been our internal laboratory reference. RESULTS: Both rabeprazole 20 mg and 40 mg, given once daily, normalized reflux time, with decreases of 79% and 92% in acid exposure by day 7. Both dosages also decreased the mean total number of reflux episodes and the number of episodes lasting > 5 min, with no significant differences between dosages for any reflux parameter. Mean gastric pH increased with 20 mg from 1.86 at baseline to 3.71 on day 1 and 4.17 on day 7. Rabeprazole 40 mg once daily increased gastric pH from 2.01 to 4.37 on day 1, and to 4.65 on day 7. Safety analyses revealed no significant acute side-effects for either dosage. CONCLUSIONS: Pathological oesophageal acid exposure was normalized with both 20 mg and 40 mg dosages of rabeprazole, and the effects of these two doses did not differ. Rabeprazole was well-tolerated in this short-term study.     

Milnacipran. A review of its use in depression

Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50 mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in- or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100 mg twice daily was as effective as fluoxetine 20 mg once daily or fluvoxamine 100 mg twice daily in 4- to 12-week studies. At a dosage of 50 then 100 mg daily it was also as effective as mianserin 30 then 60 mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. CONCLUSIONS: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder.     

Initial and repeat screening for Chlamydia trachomatis during pregnancy

BACKGROUND: We examined the efficacy and safety of three different dosages of venlafaxine hydrochloride (75, 225, and 375 mg/day) in a multicenter, randomized, double-blind, placebo-controlled, four-group study. METHOD: Outpatients, 18 to 65 years old, who met DSM-III criteria for major depression were included (N = 358 randomized; 194 completed). Of the total patients completing the trial, 59%, 56%, 51%, and 51% were in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. The primary outcome measures were the Hamilton Rating Scale for Depression (HAM-D21) total, HAM-D21 depression item, Montgomery-Asberg Depression Rating Scale total, and Clinical Global Impressions scale. RESULTS: Each dosage of venlafaxine was associated with statistically significant improvement as compared with placebo, based on the intent-to-treat sample. The two higher dosages were associated with a modestly greater antidepressant response than was the 75-mg dosage. Nausea, dizziness, somnolence, and anorexia were the most common adverse events attributable to venlafaxine. Since headache occurred at a similar frequency in both the drug and placebo groups, we did not consider it to be attributable to venlafaxine use. Withdrawal from the study due to adverse events occurred in 5%, 17%, 24%, and 30% of the patients in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. CONCLUSION: Venlafaxine, at dosages of 75-375 mg/day, is an effective and well-tolerated antidepressant. With increasing dosage, greater efficacy and possibly more adverse effects will occur.     

Mometasone furoate. A review of its intranasal use in allergic rhinitis

Mometasone furoate is a synthetic corticosteroid which has been evaluated for intranasal use in the treatment of adults and children with allergic rhinitis. In several large, well-controlled clinical trials, mometasone furoate 200 micrograms administered once daily as an aqueous intranasal spray was significantly more effective than placebo in controlling the symptoms associated with moderate to severe seasonal or perennial allergic rhinitis. Mometasone furoate was as effective as twice-daily beclomethasone dipropionate or once-daily fluticasone propionate in the treatment of perennial allergic rhinitis, and was as effective as twice-daily beclomethasone dipropionate and slightly more effective than once-daily oral loratadine in the treatment of seasonal allergic rhinitis. Mometasone furoate was also as effective as twice-daily beclomethasone dipropionate or once-daily budesonide, and significantly more effective than placebo in the prophylaxis of seasonal allergic rhinitis. The onset of action of mometasone furoate was approximately 7 hours in patients with seasonal allergic rhinitis. Mometasone furoate was as well tolerated as beclomethasone dipropionate, fluticasone propionate and budesonide in clinical trials, with an overall incidence of adverse events similar to placebo. Adverse events were generally mild to moderate and of limited duration. The most common adverse events associated with mometasone furoate therapy were nasal irritation and/or burning, headache, epistaxis and pharyngitis. Intranasal or oral mometasone furoate had no detectable effect on hypothalamic-pituitary-adrenal axis function in studies of < or = 1 year in duration. CONCLUSIONS: Mometasone furoate is a well tolerated intranasal corticosteroid with minimal systemic activity and an onset of action of < or = 7 hours. It is effective in the prophylaxis and treatment of seasonal allergic rhinitis and the treatment of perennial allergic rhinitis in patients with moderate to severe symptoms.     

Short report: ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design. The East Germany Collaborative Trial Group

OBJECTIVE: To identify appropriate dosages of ramipril and hydrochlorothiazide (HCT) when given in combination once a day for the treatment of essential hypertension. DESIGN: A 2- or 4-week placebo run-in followed by 6-week, double-blind, parallel-group phase: 4 x 3 factorial (2.5, 5 and 10 mg ramipril; 12.5 and 25 mg HCT; all six combinations; placebo). SETTING: Office practice (21 centres). PATIENTS AND PARTICIPANTS: Patients with mild-to-moderate essential hypertension (World Health Organization stage I-II; supine diastolic blood pressure 100-115 mmHg in last 2 weeks of run-in): 581 enrolled, 534 randomly assigned to double-blind therapy and 517 completed. MAIN OUTCOME MEASURES: Reduction in supine and standing blood pressure. RESULTS: In pairwise comparisons, the combinations of 5 mg ramipril with 12.5 and 25 mg HCT and 10 mg ramipril with 12.5 mg HCT consistently produced significantly greater blood pressure reductions than their respective components. Response surface analyses were performed, and a stairstep model was constructed to characterize the shape of the dose-response surface. The combinations involving 5 and 10 mg ramipril with 12.5 and 25 mg HCT were again more effective than their components. Withdrawals and adverse effects were minimal for all treatments. A large drop in serum potassium was observed on 25 mg HCT, but not on combination therapy. Addition of ramipril appeared to reduce the hyperuricaemic effect of HCT. CONCLUSIONS: Several dosage combinations of ramipril plus HCT produced significantly greater blood pressure reductions than the monotherapies at the same dosages. Overall, the combination of 5 mg ramipril and 25 mg HCT gave the best mean reduction. Combination therapy with ramipril plus HCT was safe and effective for patients with mild-to-moderate essential hypertension.     

Randomized trial of recombinant human interleukin-3 versus placebo in prevention of bone marrow depression during first-line chemotherapy for ovarian carcinoma

PURPOSE: To determine whether recombinant human interleukin-3 (rhIL-3) reduces bone marrow depression and improves chemotherapeutic schedule adherence in ovarian cancer patients receiving first-line combination chemotherapy. PATIENTS AND METHODS: In a randomized multicenter study, 185 patients received carboplatin (dose based on projected area under the concentration-time curve [AUC]=4) and cyclophosphamide (750 mg/m2) day 1, every 3 weeks for six cycles. Patients were randomized to receive rhIL-3 (5 microg/kg) or placebo once daily subcutaneously on days 3 to 12. RESULTS: Adherence to chemotherapeutic regimen, mean chemotherapy cycle length, tumor response rate, and median survival at 24 months did not differ between groups. The number of side effects-primarily allergic reactions, flu-like symptoms and fever-were higher in the rhIL-3 group, which resulted in 21 discontinuations compared with one in the placebo group. Compared with placebo, the rhIL-3 group had higher platelet counts day 1 of cycles 2 to 6. The number of patients with World Health Organization (WHO) grade IV thrombocytopenia or number of platelet transfusions did not differ. Leukocyte counts differed only in cycles 1 and 2 between groups. The leukocyte nadir occurred earlier in the rhIL-3 (day 12) than in the placebo group (day 15, P=.006). Leukocytes and neutrophils were only higher in the rhIL-3 group day 1 of cycle 2. In cycles 4 and 5, more patients with WHO grade IV neutropenia received rhIL-3 (P < .005). Eosinophil counts were higher day 1 of cycles 2 to 6 in the rhIL-3 group (P < .0001). CONCLUSION: rhIL-3 had stimulatory hematopoietic effects. This did not result either in reduction of platelet transfusions or in improvement of chemotherapeutic schedule adherence. There were more side effects in the rhIL-3 group than in the placebo group. rhIL-3 at 5 microg/kg/d is, therefore, not of clinical benefit in this chemotherapeutic regimen.     

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group

BACKGROUND: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. OBJECTIVES: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response. METHODS: This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change including caregiver information (CIBIC plus). RESULTS: A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P<.001); 0.3 and 0.4 units for CIBIC plus (P< or =.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P< or =.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (+/-SEM) donepezil plasma concentrations at study end point were 25.9 +/- 0.7 ng/mL and 50.6 +/- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (+/-SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% +/- 0.9% and 74.7% +/- 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P<.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P<.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. CONCLUSION: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease.     

Lack of hypothalamic-pituitary-adrenal axis suppression with once-daily or twice-daily beclomethasone dipropionate aqueous nasal spray administered to patients with allergic rhinitis

The potential for a newly developed, double-strength (0.084%) beclomethasone dipropionate (BDP) aqueous (AQ) nasal suspension to produce effects associated with exposure to systemic corticosteroids was assessed by the plasma cortisol response to cosyntropin stimulation induced by a 6-hour intravenous infusion of 250 micrograms of cosyntropin in 500 mL of normal saline. Sixty-four patients with allergic rhinitis were enrolled in this study. Patients were randomly assigned to one of the following four treatment groups: (1) BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily; (2) BDP AQ (0.042%) nasal spray 168 micrograms twice daily; (3) placebo nasal spray twice daily; or (4) oral prednisone 10 mg once daily in the morning. After 36 consecutive days of treatment, there was a significant (P < 0.01) difference in the plasma cortisol response to cosyntropin stimulation between the prednisone and placebo groups; however, there were no significant differences between the BDP AQ Forte or the BDP AQ groups compared with the placebo group. Secondary analyses comparing BDP AQ Forte administered as 336 micrograms once daily with BDP AQ administered as 168 micrograms twice daily showed no significant differences in plasma cortisol responses to cosyntropin stimulation. No serious adverse events were reported. Adverse events consisted of headache, pharyngitis, or nasal irritation, with headache being reported most frequently. These adverse events were similarly distributed among active treatment groups and were similar to placebo. No clinically relevant changes were observed in any treatment group in findings on clinical laboratory tests, physical examination, or electrocardiography. Vital signs, obtained daily, were consistent with values observed in healthy individuals. No patient exhibited signs of oral candidiasis. All patients met the plasma cortisol concentration criteria for discharge relative to expected hypothalamic-pituitary-adrenal axis function. In conclusion, there were no significant differences in plasma cortisol responses to cosyntropin stimulation between groups of patients with allergic rhinitis treated with either BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily or BDP AQ (0.042%) nasal spray 168 micrograms twice daily compared with the placebo group. These results indicate that the dosing regimens of BDP AQ nasal suspensions used in this study lack systemic effects and are safe and well tolerated.